Multiple myeloma (MM) is a plasma cell disorder that accounts for approximately 10% of all hematologic malignancies. Reversible proteasome inhibitor bortezomib (BTZ) in combination with other agents represents a major strategy for MM treatment. Approved in 2012, irreversible proteasome inhibitor carfilzomib (CFZ) demonstrated promising results in relapsed/refractory MM tumors and more potently induced death in MM cells than BTZ. Although the overall survival of MM patients has substantially increased, the disease remains incurable. The mechanisms of BTZ and CFZ cytotoxicity in MM cells are far from being understood. The ultimate goal of this proposal is to characterize such mechanisms and to identify novel targets for MM intervention. Recently, we have demonstrated that BTZ induces death in MM cells in part via epigenetic upregulation of the levels of Kruppel-like transcription factor 9 (KLF9). Moreover, KLF9 mRNA levels in MM cells isolated from patients prior to BTZ therapy (as assessed by microarrays) correlated with good response to BTZ treatment. CFZ demonstrated higher cytotoxicity than BTZ. We showed via head-to-head comparison that CFZ upregulates KLF9 levels even more efficiently than BTZ. Thus we will test the hypothesis that upregulation of KLF9 is a common mechanism of cytotoxicity of BTZ and CFZ, and that the higher cytotoxicity of CFZ is due to a more efficient induction of KLF9. KLF9-dependent pathways underlying cytotoxicity of BTZ and CFZ are unknown. In search for such pathways, we utilized ChIP-Seq and quantitative RT-PCR assays and discovered that KLF9 suppresses expression of genes that directly or indirectly decrease oxidative stress. Among KLF9 targets involved in response to oxidative stress, we identified two genes that demonstrated KLF9-, CFZ- and BTZ-dependent expression pattern and whose genetic or pharmacological inhibition partially recapitulates the effects induced in these cells by BTZ or CFZ. Thus, we will test the hypothesis that partial depletion of KLF9 targets mediates cytotoxicity of BTZ and CFZ, while more efficient genetic or pharmacological inhibition of these targets reduces tumor burden and increases efficacy of BTZ or CFZ in a mouse model of MM.